Is SLC9A1 p.Pro331= (c.993G>A) pathogenic?

SLC9A1 p.Pro331= (c.993G>A) is classified Likely benign in SLC9A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). Ultra-rare (popmax 0.0187%, sas).

How common is SLC9A1 p.Pro331= (c.993G>A) in the general population?

SLC9A1 p.Pro331= (c.993G>A) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

SLC9A1 p.Pro331=

c.993G>A · VCV4706629

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP 2.1
Overall
CADD	13.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,084 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00725% 117/1,613,766 alleles · ultra-rare exomes 106/1,461,680 · genomes 11/152,086 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.145%	688
Remaining individualsnot grpmax-eligible	0.0272%	3,676
South Asiangrpmax	0.0187%	5,358
Admixed American	0.00667%	14,998
European (non-Finnish)	0.00271%	36,875
African / African-American	0.00267%	37,441
East Asian	0.00223%	44,878
Finnishnot grpmax-eligible	0.00157%	63,840

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SLC9A1
Protein: p.Pro331=
Coding: c.993G>A
MANE Select: NM_003047
Type: single nucleotide variant
Location: chr1:27109598 (GRCh38)
Gene constraint: LOEUF 0.473 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.92 · 21 PDB
Residue 331: an α-helix

Full SLC9A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SLC9A1 p.Arg700Cys Uncertain significance ★★ ⚠ same type
SLC9A1 p.Asp59Val Uncertain significance ★★ ⚠ same type
SLC9A1 p.Asp758Asn Uncertain significance ★★ ⚠ same type
SLC9A1 p.Asp759Asn Uncertain significance ★★ ⚠ same type
SLC9A1 p.Cys212Phe Uncertain significance ★★ ⚠ same type
SLC9A1 p.Glu756Lys Uncertain significance ★★ ⚠ same type
SLC9A1 p.Gly231Ser Uncertain significance ★★ ⚠ same type
SLC9A1 p.Gly287Ser Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/slc9a1-p-pro331 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown